Novel Enantiomeric Pure Beta Agonists, Manufacturing and Use as a Medicament Thereof

ABSTRACT

The present invention relates to enantiomerically pure compounds of formula 1  
                 
 
wherein the groups m, n, B, X, R 1 , m and Y m-  may have the meanings given in the claims and specification, methods for preparing them and their use as pharmaceutical compositions, particularly as pharmaceutical compositions for the treatment of respiratory complaints.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of EP06111338.7, filed Mar. 17, 2006;EP06111191.0, filed Mar. 15, 2006; and EP06111342.9, filed Mar. 17,2006.

FIELD OF THE INVENTION

The present invention relates to enantiomerically pure compounds offormula 1

wherein the groups m, n, B, X, R¹, m and Y^(m-) may have the meaningsgiven in the claims and specification, methods for preparing them andtheir use as pharmaceutical compositions, particularly as pharmaceuticalcompositions for the treatment of respiratory complaints.

BACKGROUND OF THE INVENTION

Betamimetics (β-adrenergic substances) are discussed in U.S. Pat. No.4,460,581, which proposes betamimetics for the treatment of a range ofdiseases.

For drug treatment of diseases it is often desirable to preparemedicaments with a longer duration of activity. As a rule, this ensuresthat the concentration of the active substance in the body needed toachieve the therapeutic effect is guaranteed for a longer period withoutthe need to re-administer the drug at frequent intervals. Moreover,giving an active substance at longer time intervals contributes to thewell-being of the patient to a high degree.

It is particularly desirable to prepare a pharmaceutical compositionwhich can be used therapeutically by administration once a day (singledose). The use of a drug once a day has the advantage that the patientcan become accustomed relatively quickly to regularly taking the drug atcertain times of the day.

The aim of the present invention is therefore to provide betamimeticswhich on the one hand confer a therapeutic benefit in the treatment ofrespiratory complaints and are also characterized by a longer durationof activity and can thus be used to prepare pharmaceutical compositionswith a longer duration of activity. A further objective of the presentinvention is to prepare betamimetics which, by virtue of theirlong-lasting effect, can be used to prepare a drug for administrationonce a day for treating respiratory complaints. Another objective of theinvention, apart from those mentioned above, is to prepare betamimeticswhich are not only exceptionally potent but are also characterized by ahigh degree of selectivity with respect to the β₂-adrenoceptor. Inaddition, the invention sets out to prepare betamimetics which becauseof their physicochemical properties can be used in particular forpreparing pharmaceutical formulations which are particularly suitablefor administration by inhalation. The invention also relates to thepreparation of betamimetics, which in addition to having theabove-mentioned properties, are also particularly suitable for preparinginhalable powders and suspension aerosols.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Differential scanning calorimetry plot of Example 5.

FIG. 2: Differential scanning calorimetry plot of Example 16.

FIG. 3: Differential scanning calorimetry plot of Example 27.

DETAILED DESCRIPTION OF THE INVENTION

The above-mentioned objectives are achieved with compounds of generalformula 1. The present invention relates to enantiomerically purecompounds of formula 1:

wherein

-   n denotes 1, 2, 3 or 4;-   X denotes CH₂, CO, NR², S or O;-   B denotes a double-bonded group of formula CR³R⁴—O;-   R¹ denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl, O—C₁₋₆-haloalkyl, halogen, OH, CN,    NO₂, O—C₁₋₆-alkyl, COOH or COO—C₁₋₄-alkyl;-   R² denotes H, C₁₋₆-alkyl, C₁₋₄-alkylene-C₆₋₁₀-aryl or    C₁₋₄-alkylene-C₃₋₆-cycloalkyl, preferably H or C₁₋₆-alkyl;-   R³ denotes H or C₁₋₆-alkyl;-   R⁴ denotes H or C₁₋₆-alkyl;-   Y^(m-) an anion with m negative charges, preferably an anion with m    negative charges selected from among chloride, bromide, iodide,    sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,    benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate,    oxalate, succinate, ethanedisulphonate, propanedisulphonate,    benzoate and p-toluenesulphonate,-   m denotes 1 or 2    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

The enantiomerically pure compound shown in formula 1 corresponds to theR-enantiomer.

The compounds of formula 1 consist of a molecule with a single positivecharge and an anion Y^(m-) with a single charge or a corresponding 1/mpart of an anion Y^(m-) with a single charge. Thus, for example, twomolecules of formula

wherein the groups n, B, X and R¹ may have the meanings given above, maybe in a crystalline formation with an anion Y^(m-) having a doublecharge wherein m=2, such as e.g. ethanedisulphonate orpropanedisulphonate.

In one embodiment the enantiomerically pure compounds of formula 1, aresubstituted as follows:

-   n denotes 1, 2 or 3; preferably 2 or 3-   X denotes CH₂, CO, NR², S or O;-   B denotes a double-bonded group of formula CR³R⁴—O;-   R¹ denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl, O—C₁₋₆-haloalkyl, halogen, OH, CN,    NO₂, O—C₁₋₆-alkyl, COOH, COO—C₁₋₄-alkyl; preferably H, C₁₋₆-alkyl,    C₁₋₆-haloalkyl, C₃₋₆-cycloalkyl, halogen, OH, CN, NO₂, O—C₁₋₆-alkyl,    COOH or COO—C₁₋₄-alkyl;-   R² denotes H, C₁₋₄-alkyl, C₁₋₂-alkylene-C₃₋₆-cycloalkyl, phenylethyl    or benzyl, preferably H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl-methyl,    particularly preferably H, methyl or cyclopropylmethyl;-   R³ denotes H or C₁₋₄-alkyl; preferably H or methyl;-   R⁴ denotes H or C₁₋₄-alkyl; preferably H or methyl;-   Y^(m-) denotes an anion with m negative charges, preferably an anion    with m negative charges selected from among chloride, bromide,    iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, ethanedisulphonate, benzoate and    p-toluenesulphonate,-   m denotes 1 or 2,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

In another embodiment enantiomerically pure compounds of formula I, areas follows:

-   n denotes 2 or 3-   X denotes CH₂, CO, NR², S or O;-   B denotes a double-bonded group of formula CR³R⁴—O;-   R¹ denotes H, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₃₋₆-cycloalkyl, halogen,    OH, CN, NO₂, O—C₁₋₆-alkyl, COOH or COO—C₁₋₄-alkyl;-   R² denotes H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl-methyl, particularly    preferably H, methyl or cyclopropylmethyl;-   R³ denotes H or methyl;-   R⁴ denotes H or methyl;-   Y^(m-) denotes an anion with m negative charges, preferably an anion    with m negative charges selected from among chloride, bromide,    iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, ethanedisulphonate, benzoate and    p-toluenesulphonate,-   m denotes 1 or 2,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

In an embodiment enantiomerically pure compounds of formula 1, are asfollows:

-   n denotes 2 or 3-   X denotes CH₂, CO, NR², S or O;-   B denotes a double-bonded group of formula CR³R⁴—O;-   R¹ denotes H, methyl, ethyl, propyl, CF₃, CH₂F, CH₂CF₃, fluorine,    chlorine, bromine, OH, methoxy, ethoxy, COOH or COOMe;-   R² denotes H, methyl, ethyl or propyl;-   R³ denotes H or methyl;-   R⁴ denotes H or methyl;-   Y^(m-) denotes an anion with m negative charges, preferably an anion    with m negative charges selected from among chloride, bromide,    iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, ethanedisulphonate, benzoate and    p-toluenesulphonate,-   m denotes 1 or 2,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

In an additional embodiment enantiomerically pure compounds of formula1, are as follows:

-   n denotes 2 or 3-   X denotes CH₂, CO, NR², S or O;-   B denotes a double-bonded group of formula CH₂—O;-   R¹ denotes H, methyl, ethyl, propyl, CF₃, CH₂F, CH₂CF₃, fluorine,    chlorine, bromine, OH, methoxy, ethoxy, COOH or COOMe;-   R² denotes H, methyl, ethyl or propyl;-   Y^(m-) denotes an anion with m negative charges, preferably an anion    with m negative charges selected from among chloride, bromide,    iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, ethanedisulphonate, benzoate and    p-toluenesulphonate,-   m denotes 1 or 2,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

In an embodiment enantiomerically pure compounds of formula I, are asfollows:

-   n denotes 2 or 3-   X denotes NR² or O;-   B denotes a double-bonded group of formula CH₂—O;-   R¹ denotes H, methyl, ethyl, propyl, CF₃, CH₂F or CH₂CF₃;-   R² denotes H, methyl, ethyl or propyl;-   Y^(m-) denotes an anion with m negative charges, preferably an anion    with m negative charges selected from among chloride, bromide,    iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, ethanedisulphonate, benzoate and    p-toluenesulphonate,-   m denotes 1 or 2,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

In another embodiment enantiomerically pure compounds of formula 1, areas follows:

-   n denotes 2-   X denotes NH;-   B denotes a double-bonded group of formula CH₂—O;-   R¹ denotes H, methyl or CF₃;-   Y^(m-) denotes an anion with m negative charges, preferably an anion    with m negative charges selected from among chloride, bromide,    iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,    acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,    tartrate, oxalate, succinate, ethanedisulphonate, benzoate and    p-toluenesulphonate,-   m denotes 1 or 2,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

In another embodiment enantiomerically pure compounds of formula I, arepresented wherein n=2 denotes and X, B, R¹, R², m and Y^(m-) may havethe meaning given hereinbefore, optionally in the form of the tautomers,mixtures of the tautomers, hydrates or solvates thereof.

In an embodiment enantiomerically pure compounds of formula 1, whereinX═NR² and n, X, B, R¹, R², m and Y^(m-) may have the meaning givenhereinbefore, optionally in the form of the tautomers, mixtures of thetautomers, hydrates or solvates thereof.

In an embodiment enantiomerically pure compounds of formula 1, whereinX═NH and n, X, B, R¹, m and Y^(m-) may have the meaning givenhereinbefore, optionally in the form of the tautomers, mixtures of thetautomers, hydrates or solvates thereof.

In another embodiment enantiomerically pure compounds of formula I,wherein B denotes a double-bonded group of formula CH₂—O and n, X, R¹,R², m and Y^(m-) may have the meaning given hereinbefore, optionally inthe form of the tautomers, mixtures of the tautomers, hydrates orsolvates thereof.

Compounds of the above formula 1 may be selected from but are notlimited to the following:

-   R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    maleate-   R-6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    tartrate-   R-6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    tartrate    -   R-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one        tartrate-   R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate-   R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate optionally in the form of the tautomers,    mixtures of the tautomers, hydrates or solvates thereof.

Additionally, compounds of the above formula 1 may be selected from butare not limited to the following:

-   R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate    -   R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one        hemi-ethanedisulphonate    -   R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one        hemi-ethanedisulphonate    -   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one        hemi-ethanedisulphonate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate,    optionally in the form of the tautomers, mixtures of the tautomers,    hydrates or solvates thereof.

Compounds of the above formula 1 may be selected from but are limited tothe following:

-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    maleate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    tartrate-   R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one    hemi-ethanedisulphonate, optionally in the form of the tautomers,    mixtures of the tautomers, hydrates or solvates thereof.

Enantiomerically pure compounds of general formula 1 are found incrystalline form, optionally in the form of the crystalline tautomers,crystalline hydrates or crystalline solvates thereof Examples includethe above enantiomerically pure, crystalline compounds of generalformula 1, optionally in the form of the crystalline tautomers,crystalline hydrates or crystalline solvates thereof, which are furthercharacterised in that they are crystalline compounds which are presentin only a single crystal modification.

By the term a single crystal modification are meant crystallinecompounds of formula 1 which do not constitute a mixture of any crystalmodifications which may exist. The compounds of formula 1 according tothe invention are characterised by their versatility of use in thetherapeutic field. The compounds according to formula 1 are used due totheir pharmaceutical activity as betamimetics.

In another aspect the present invention correspondingly relates to theabove-mentioned enantiomerically pure compounds of formula 1 aspharmaceutical compositions. The present invention further relates tothe use of the above-mentioned compounds of general formula 1 forpreparing a pharmaceutical composition for the treatment of respiratorycomplaints. The present invention relates to the use of theabove-mentioned compounds of general formula 1 for preparing apharmaceutical composition for the treatment of respiratory complaints,which are selected from among obstructive pulmonary diseases of variousorigins, pulmonary emphysema of various origins, restrictive pulmonarydiseases, interstitial pulmonary diseases, cystic fibrosis, bronchitisof various origins, bronchiectasis, ARDS (adult respiratory distresssyndrome) and all forms of pulmonary oedema.

The compounds of formula 1 are used to prepare a pharmaceuticalcomposition for the treatment of obstructive pulmonary diseases selectedfrom among COPD (chronic obstructive pulmonary disease), bronchialasthma, paediatric asthma, severe asthma, acute asthma attacks andchronic bronchitis, one example according to the invention is to use thecompounds of formula 1 for preparing a pharmaceutical composition forthe treatment of bronchial asthma.

In another nonlimiting example, the compounds of formula 1 are used toprepare a pharmaceutical composition for the treatment of pulmonaryemphysema which has its origins in COPD (chronic obstructive pulmonarydisease) or α1-proteinase inhibitor deficiency.

In addition, the compounds of formula 1 may be used to prepare apharmaceutical composition for the treatment of restrictive pulmonarydiseases selected from among allergic alveolitis, restrictive pulmonarydiseases triggered by work-related noxious substances, such asasbestosis or silicosis, and restriction caused by lung tumours, such asfor example lymphangiosis carcinomatosa, bronchoalveolar carcinoma andlymphomas.

also In an additional nonlimiting example, the compounds of formula 1are used to prepare a pharmaceutical composition for the treatment ofinterstitial pulmonary diseases selected from among pneumonia caused byinfections, such as for example infection by viruses, bacteria, fungi,protozoa, helminths or other pathogens, pneumonitis caused by variousfactors, such as for example aspiration and left heart insufficiency,radiation-induced pneumonitis or fibrosis, collagenoses, such as forexample lupus erythematodes, systemic sclerodermy or sarcoidosis,granulomatoses, such as for example Boeck's disease, idiopathicinterstitial pneumonia or idiopathic pulmonary fibrosis (IPF).

The compounds of general formula 1 may be used to prepare apharmaceutical composition for the treatment of cystic fibrosis ormucoviscidosis.

also In addition, the compounds of general formula 1 may be used toprepare a pharmaceutical composition for the treatment of bronchitis,such as for example bronchitis caused by bacterial or viral infection,allergic bronchitis and toxic bronchitis.

also In another nonlimiting embodiment, the compounds of general formula1 are used to prepare a pharmaceutical composition for the treatment ofbronchiectasis. Another example includes, the compounds of generalformula 1 being used to prepare a pharmaceutical composition for thetreatment of ARDS (adult respiratory distress syndrome).

As an example, the compounds of general formula 1 may be used to preparea pharmaceutical composition for the treatment of pulmonary edema, forexample toxic pulmonary oedema after aspiration or inhalation of toxicsubstances and foreign substances.

As an additional embodiment the use of the compounds of formula 1include preparing a pharmaceutical composition for the treatment ofasthma or COPD. Also of particular importance is the above-mentioned useof compounds of formula 1 for preparing a pharmaceutical composition foronce-a-day treatment of inflammatory and obstructive respiratorycomplaints, particularly for the once-a-day treatment of asthma or COPD.

The present invention also relates to a process for the treatment of theabove-mentioned diseases, characterised in that one or more of theabove-mentioned compounds of general formula 1 are administered intherapeutically effective amounts. The present invention further relatesto processes for the treatment of asthma or COPD, characterised in thatone or more of the above-mentioned compounds of general formula 1 areadministered once a day in therapeutically effective amounts.

Terms and Definitions Used

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. Examples of these include but are notlimited to: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. Theabbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionallyalso be used for the above-mentioned groups. Unless otherwise stated,the definitions propyl, butyl, pentyl and hexyl include all the possibleisomeric forms of the groups in question. Thus, for example, propylincludes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyland tert-butyl etc.

By the term “C₂₋₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Nonlimiting examples of these include: ethenyl or vinyl,propenyl, butenyl, pentenyl, or hexenyl. Unless otherwise stated, thedefinitions propenyl, butenyl, pentenyl and hexenyl include all thepossible isomeric forms of the groups in question. Thus, for example,propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.

By the term “C₂₋₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples of these include: ethynyl, propynyl, butynyl,pentynyl, or hexynyl. Unless otherwise stated, the definitions propynyl,butynyl, pentynyl and hexynyl include all the possible isomeric forms ofthe groups in question. Thus, for example, propynyl includes 1-propynyland 2-propynyl, butynyl includes 1,2- and 3-butynyl,1-methyl-1-propynyl, 1-methyl-2-propynyl etc.

By the term “C₃₋₆-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examplesof these include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.Unless otherwise stated, the cyclic alkyl groups may be substituted byone or more groups selected from among methyl, ethyl, iso-propyl,tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “C₁₋₆-haloalkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, which are substituted by one or more halogen atoms. By theterm “C₁₋₄-alkyl” are meant branched and unbranched alkyl groups with 1to 4 carbon atoms, which are substituted by one or more halogen atoms.Alkyl groups with 1 to 4 carbon atoms are preferred. Examples of theseinclude: CF₃, CHF₂, CH₂F, CH₂CF₃.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6 or 10 carbon atoms. Examples of theseinclude: phenyl or naphthyl, the preferred aryl group being phenyl.Unless otherwise stated, the aromatic groups may be substituted by oneor more groups selected from among methyl, ethyl, iso-propyl,tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

Halogen within the scope of the present invention denotes fluorine,chlorine, bromine or iodine. Unless stated to the contrary, fluorine,chlorine and bromine are the preferred halogens.

The term enantiomerically pure describes within the scope of the presentinvention compounds of formula 1 which are present in an enantiomericalpurity of at least 85% ee, preferably at least 90% ee, particularlypreferably >95% ee. The term ee (enantiomeric excess) is known in theart and describes the optical purity of chiral compounds.

The compounds according to the invention may be prepared by the methodoutlined in Scheme 1.

EXAMPLES Synthesis of Intermediate Stages

Intermediate 1: tert-butyl (3-amino-3-methyl-butyl)-carbamate: 23.6 g(117 mmol) tert-butyl (1,1-dimethyl-3-oxo-propyl)-carbamate in 700 mLethanolic ammonia solution are treated in the presence of 3.5 g Raneynickel at ambient temperature with 3 bar hydrogen pressure until no moreeduct can be detected by thin layer chromatography. The catalyst isfiltered off and the solvent is eliminated by distillation.

Yield: 22.7 g (96%); mass spectroscopy: [M+H]⁺=203.

Intermediate 2:1-(3-amino-1,1-dimethyl-proypl)-6-methyl-1,3-dihydro-benzimidazol-2-one

A)tert-butyl[3-methyl-3-(5-methyl-2-nitro-phenylamino)-butyl]-carbamate:2.0 g (12.9 mmol) 3-fluoro-4-nitro-toluene, 2.6 g (13.0 mmol) tert-butyl(3-amino-3-methyl-ambient temperature in 20 mL DMF. The solvent isdistilled off and the residue is combined with ethyl acetate. Themixture is washed repeatedly with water, dried with sodium sulphate andthe solvent is eliminated.

Yield 4.8 g, mass spectroscopy: [M+H]⁺=338.

b)tert-butyl[3-(2-amino-5-methyl-phenylamino)-3-methyl-butyl]-carbamate:4.71 g (14.0 mmol)tert-butyl[3-methyl-3-(5-methyl-2-nitro-phenylamino)-butyl]-carbamateare dissolved in 110 mL methanol and hydrogenated in the presence of 340mg palladium on charcoal (10%) at ambient temperature. Then the catalystis separated off and the solvent is distilled off. Yield: 3.72 g (87%);mass spectroscopy: [M+H]⁺=308.

c)tert-butyl[3-methyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyl]-carbamate:1.76 g (5.7 mmol)tert-butyl[3-(2-amino-5-methyl-phenylamino)-3-methyl-butyl]-carbamateare dissolved in 35 mL THF, combined with 2.1 g (12.7 mmol)1,1′-carbonyldi-(1,2,4-triazole) and stirred overnight. The solvent isdistilled off and the residue is dissolved in ethyl acetate. Thesolution is washed successively with potassium hydrogen sulphatesolution and sodium chloride solution and dried with sodium sulphate.The residue is chromatographed (silica gel; dichloromethane with 0-16%methanol:ammonia=9:1) and the crude product thus obtained is stirredwith diethyl ether.

Yield: 1.12 g (59%); mass spectroscopy: [M+H]⁺=334.

d)1-(3-amino-1,1-dimethyl-proypl)-6-methyl-1,3-dihydro-benzimidazol-2-one:A solution of 1.50 g (4.5 mmol)tert-butyl[3-methyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-butyl]-carbamatein 100 mL dioxane is combined with 10 mL of 4 molar hydrochloric acid indioxane and then heated to 90° C. for 90 minutes, during which time awhite precipitate is formed. After cooling to ambient temperature thesolvent is distilled off and the residue is stirred in diethyl ether.

Yield: 1.04 g (86%; hydrochloride); mass spectroscopy: [M+H]⁺=234.

Intermediate 3:1-(3-amino-3-methyl-butyl)-5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one

a)tert-butyl[3-methyl-3-(2-nitro-4-trifluoromethyl-phenylamino)-butyl]-carbamate:is prepared analogously to Method 2a) from a total of 3.25 g (15.5 mmol)1-fluoro-2-nitro-4-trifluoromethyl-benzene and 2.74 g (13.5 mmol)tert-butyl (3-amino-3-methyl-butyl)-carbamate.

Yield: 6.1 g, mass spectroscopy: [M+H]⁺=392.

b)tert-butyl[3-(2-amino-4-trifluoromethyl-phenylamino)-1,1-dimethyl-propyl]-carbamate:6.10 g (15.6 mmol)tert-butyl[3-methyl-3-(2-nitro-4-trifluoromethyl-phenylamino)-butyl]-carbamateare hydrogenated analogously to Method 2b).

Yield: 5.05 g (90%); mass spectroscopy: [M+H]⁺=362.

c)tert-butyl[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propyl]-carbamate:5.00 g (13.8 mmol)tert-butyl[3-(2-amino-4-trifluoromethyl-phenylamino)-1,1-dimethyl-propyl]-carbamateand 6.73 g (41.5 mmol) 1,1′-carbonyldiimidazole are reacted and workedup analogously to Method 2c).

Yield: 4.18 g (78%); mass spectroscopy: [M−H]⁺=386.

d)1-(3-amino-3-methyl-butyl)-5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one:method of preparation is analogously to Method 2d) from 2.89 g (7.5mmol) tert-butyl[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propyl]-carbamate.

Yield: 1.60 g (66%; hydrochloride); mass spectroscopy: [M+H]⁺=288

Intermediate 4: 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one

a) 1-iodo-4-methyl-nitro-pentane: A solution of 44.7 mL (352 mmol)chlorotrimethylsilane and 50 mL acetonitrile is added dropwise to 26.0 g(177 mmol) 1-methyl-4-nitro-pentan-1-ol and 52.8 g (352 mmol) sodiumiodide in 350 mL acetonitrile. Then the mixture is heated to 50° C. for4 hours, then the solvent is distilled off and the residue is combinedwith 500 mL diethyl ether. It is washed successively with water, sodiumthiosulphate solution and sodium chloride solution. The organic phase isdried with sodium sulphate and evaporated down. Yield: 34.2 g.

b) 3-(3-methyl-3-nitro-butyl)-3H-benzoxazol-2-one: 1.70 g (42.5 mmol)sodium hydride (60%) are added batchwise to a solution of 4.50 g (33.3mmol) benzoxazol-2-one in 50 mL DMF, while the temperature is kept below0° C. by cooling. After one hour's stirring a solution of 9.61 g (37.4mmol) 1-iodo-4-methyl-4-nitro-pentane in 20 mL DMF is added dropwisesuch that the temperature does not rise above 5° C. The mixture is leftovernight at ambient temperature with stirring and the solvent isdistilled off. The residue is taken up in ethyl acetate and washedsuccessively with water and sodium chloride solution, dried with sodiumsulphate and evaporated down. 11.0 g product are obtained. Massspectroscopy: [M+H]⁺=265.

c) 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one: 11.0 g3-(3-methyl-3-nitro-butyl)-3H-benzoxazol-2-one from the reactiondescribed above are dissolved in 130 mL ethanol and hydrogenated withRaney nickel as catalyst at 5 bar for 20 hours. The catalyst is filteredoff and the filtrate is freed from the solvent. 10% ethanolichydrochloric acid is added, the solvent is distilled off and the residueis stirred in an acetone/diethyl ether mixture.

Yield: 6.0 g (77% over 2 steps, hydrochloride); melting range=145-147°C.

Intermediate 5: 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one

a) tert-butyl[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propyl]-carbamate:4.0 g (29.6 mmol) benzoxazol-2-one are dissolved in 40 mL DMPU andcooled with an ice bath. Under protective gas 897 mg (95%; 35.5 mmol)sodium hydride is added batchwise to this solution. The reaction mixtureis heated to ambient temperature and then stirred for anotherhour. 9.85g (44.4 mmol) tert-butyl (3-amino-1,1-dimethyl-propyl)-carbamate and1.97 g (5.3 mmol) tetrabutylammonium iodide are added and the mixture isstirred overnight. The reaction is stopped by the careful addition ofsodium hydrogen carbonate solution. Ethyl acetate is added, the aqueousphase is separated off and extracted repeatedly with ethyl acetate. Thecombined organic phases are washed with sodium chloride solution, driedwith sodium sulphate and evaporated down. Purification of the residue bycolumn chromatography (silica gel; petroleum ether/ethyl acetate=7:3)yields the desired product.

Yield 4.1 g (43%); mass spectroscopy: [M+H]⁺=321.

b) 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one: 18 mL trifluoroaceticacid are added dropwise at ambient temperature to a solution of 4.0 g(12.5 mmol)tert-butyl[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propyl]-carbamate in110 mL dichloromethane. The mixture is left overnight with stirring andthen the solvent is dissolved off. The oil remaining is stirred intodiethyl ether, during which time a solid is precipitated, which isfiltered off. After further stirring with diethyl ether and filtrationthe product is obtained.

Yield: 3.63 g (65%; trifluoroacetate); mass spectroscopy: [M+H]⁺=221.

Intermediate 6:1-(3-amino-3-methyl-butyl)-4-methoxy-1,3-dihydro-benzimidazol-2-one

a) 4-methyl-4-nitro-pentan-1-ol: 50 g (0.285 mol) methyl4-methyl-4-nitro-pentanoate are dissolved in a 6:4 mixture ofTHF/ethanol (1000 mL). The solution is cooled to −10° C. and combinedwith 24.2 g (0.571 mol) lithium chloride. Then 21.6 g (0.571 mol)lithium borohydride are added batchwise. The mixture is stirred for 30minutes at −10° C. and then heated overnight to ambient temperature. Thereaction mixture is stirred for 6 hours at 60° C. and overnight atambient temperature. It is mixed with water and adjusted to pH 6 withdilute hydrochloric acid. The solvent is distilled off and the residueis combined with water. It is extracted with dichloromethane, thecombined organic phases are washed with water and ammonium chloridesolution and dried with sodium sulphate. After elimination of thesolvent the product is obtained.

Yield: 40.0 g (95%); mass spectroscopy: [M+H]⁺=148.

b) 1-iodo-4-methyl-4-nitro-pentane: 70 mL (0.544 mol)trimethylchlorosilane are added dropwise at ambient temperature to 40 g(0.272 mol) 4-methyl-4-nitro-pentan-1-ol and 81.5 g (0.544 mol) sodiumiodide in 350 mL acetonitrile. The reaction mixture is filtered,evaporated down and combined with diethyl ether. The organic phase iswashed with sodium bisulphite solution and water, dried and freed fromthe solvent.

Yield: 56.0 g (80%); mass spectroscopy: [M-NO₂]⁺=211.

c) 2-methoxy-6-nitro-phenylamine: 85% potassium hydroxide solution (11.7g, 0.179 mol) is added to a solution of 25 g (0.162 mol)2-amino-3-nitro-phenol in 200 mL DMF. Then 11.1 mL (0.178 mol)iodomethane are added dropwise and the mixture is stirred overnight atambient temperature. The reaction mixture is poured onto ice and stirredfor one hour. The precipitated product is filtered off, washed withwater and dried.

Yield: 23.8 g (87%); mass spectroscopy: [M+H]⁺=169.

d) ethyl (2-methoxy-6-nitro-phenyl)-carbamate: At reflux temperature17.1 mL (0.141 mol) trichloromethylchloroformate are added dropwise to asolution of 23.8 g (0.142 mol) 2-methoxy-6-nitro-phenylamine in 300 mLTHF and then the mixture is stirred for 4 hours at this temperature. Thesolvent is distilled off and the residue is stirred with isopropanol,whereupon a yellow solid is precipitated.

Yield: 25.0 g (73%); mass spectroscopy: [M+H]⁺=241.

e) ethyl (2-amino-6-methoxy-phenyl)-carbamate: 25.0 g (0.104 mol) ethyl(2-methoxy-6-nitro-phenyl)-carbamate are dissolved in 400 mL methanol.116.4 g (0.516 mol) SnCl₂ 2H₂O are added and the mixture is refluxed for3 hours. The reaction mixture is evaporated down, combined with sodiumcarbonate solution and filtered. The aqueous phase is repeatedlyextracted with dichloromethane and the combined organic phases arewashed with sodium chloride solution, dried and evaporated down. Theresidue that crystallises out on standing is stirred with isopropanol.

Yield: 13.0 g (59%); mass spectroscopy: [M+H]⁺=211.

f) ethyl 7-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-carboxylate: 13.0 g(0.062 mol) ethyl (2-amino-6-methoxy-phenyl)-carbamate and 10.3 mL(0.074 mol) triethylamine in 100 mL dichloromethane are added, whilecooling with ice, to a solution of 8.20 mL (0.068 mol)trichloromethylchloroformate in 50 mL dichloromethane. After 4 hoursstirring at ambient temperature the reaction mixture is poured onto iceand extracted with dichloromethane. The combined organic phases arewashed with water, dried and freed from the solvent. The residue isstirred in diethyl ether.

Yield: 9.0 g (62%); mass spectroscopy: [M+H]⁺=237.

g) 4-methoxy-1-(3-methyl-3-nitro-butyl)-1,3-dihydro-benzimidazol-2-one:4.0 g (17 mmol) ethyl7-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-carboxylate in DMF arecombined with 85% potassium hydroxide solution (3.3 g, 51 mmol) whilecooling with the ice bath. After 30 minutes a solution of 5.2 g (21mmol) 1-iodo-4-methyl-4-nitro-pentane in DMF is added and the mixture isstirred overnight at ambient temperature. The reaction mixture isdiluted with water and extracted with ethyl acetate. The combinedorganic phases are washed with water, dried and freed from the solvent.The oil remaining is purified by chromatography on a silica gel column(cyclohexane/ethyl acetate gradient).

Yield: 0.5 g (8%); mass spectroscopy: [M+H]⁺=366.

h) 1-(3-amino-3-methyl-butyl)-4-methoxy-1,3-dihydro-benzimidazol-2-one:1.4 g (4.8 mmol)4-methoxy-1-(3-methyl-3-nitro-butyl)-1,3-dihydro-benzimidazol-2-one aredissolved in methanol and hydrogenated at 3 bar in the presence of Raneynickel. The catalyst is separated off, the solvent is distilled off andthe residue is dissolved in ethanolic hydrochloric acid. The solventsare removed by distillation and the solid remaining is stirred withisopropanol.

Yield: 0.6 g (42%, hydrochloride); mass spectroscopy: [M+H]⁺=300.

Intermediate 7:1-(3-amino-3-methyl-butyl)-5-methoxy-3-methyl-1,3-dihydro-benzimidazol-2-one

a) (5-methoxy-2-nitro-phenyl)-methyl-amine: 83.5 mL (167.0 mmol) of a 2molar solution of methylamine in THF are added dropwise to 14.3 g (83.56mmol) 3-fluoro-4-nitro-anisol and 12.71 g (92.02 mmol) potassiumcarbonate in 200 mL dichloromethane. The mixture is stirred overnightand then water is added. The organic phase is washed successively withwater and ammonium chloride solution, dried and evaporated down. Theproduct remaining is stirred with hexane.

Yield: 12.7 g (84%); mass spectroscopy: [M+H]⁺=183.

b) 4-methoxy-N²-methyl-benzene-1,2-diamine: 12.5 g (68.6 mmol)(5-methoxy-2-nitro-phenyl)-methyl-amine and 77.39 g (343.0 mmol) SnCl₂2H₂O in 200 mL ethanol are refluxed for 6 hours. The reaction mixture iswashed with sodium carbonate solution, filtered and evaporated down. Theresidue is combined with water and extracted with ethyl acetate. Thecombined organic phases are washed with water, dried and freed from thesolvent. Yield: 8.0 g (77%); mass spectroscopy: [M+H]⁺=153.

c) 5-methoxy-1-methyl-1,3-dihydro-benzimidazol-2-one: 8.0 g (52.56 mmol)4-methoxy-N²-methyl-benzene-1,2-diamine and 8.7 mL (63.00 mmol)triethylamine are dissolved in 100 mL dichloromethane and added dropwiseto 7 mL (58.00 mmol) trichloromethylchloroformate in 50 mLdichloromethane. The reaction mixture is stirred overnight at ambienttemperature, then poured into ice water and extracted withdichloromethane. The combined organic phases are washed with water,dried and evaporated down. The product remaining is stirred with diethylether.

Yield: 4.2 g (45%); mass spectroscopy: [M+H]⁺=179.

d)5-methoxy-3-methyl-1-(3-methyl-3-nitro-butyl)-1,3-dihydro-benzimidazol-2-one:1.1 g (28 mmol) 60% sodium hydride are added to 2.5 g (14 mmol)5-methoxy-1-methyl-1,3-dihydro-benzimidazol-2-one in 30 mL DMF whilecooling with the ice bath. After 30 minutes a solution of1-iodo-4-methyl-4-nitro-pentane in 20 mL DMF is piped in and the mixtureis stirred overnight. It is diluted with water and extracted with ethylacetate. The combined organic phases are washed with water, dried andevaporated down. The product remaining is stirred with diethyl ether.

Yield: 2.7 g (63%); mass spectroscopy: [M+H]⁺=308.

e)1-(3-amino-3-methyl-butyl)-5-methoxy-3-methyl-1,3-dihydro-benzimidazol-2-one:2.7 g (8.7 mmol)5-methoxy-3-methyl-1-(3-methyl-3-nitro-butyl)-1,3-dihydro-benzimidazol-2-oneand 9.93 g (44.0 mmol) SnCl₂ 2H₂O in 200 mL ethanol are refluxed for 3hours. The reaction mixture is evaporated down, combined with sodiumcarbonate solution and filtered. The filtrate is extracted with ethylacetate and the combined organic phases are washed with water, dried andfreed from the solvent. The residue is dissolved in ethanol and thesolution is combined with ethereal hydrochloric acid. After the solventhas been dissolved off the product remaining is stirred withdiisopropylether.

Yield: 0.7 g (29%); mass spectroscopy: [M+H]⁺=278.

Intermediate 8:3-(4-amino-4-methyl-pentyl)-5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one

a) (4-fluoro-2-nitro-phenyl)-methyl-amine: 157 ml (314 mmol) of a 2molar solution of methylamine in THF are added dropwise to 25 g (157mmol) 2,4-difluoro-nitrobenzene and 23.9 g (173 mmol) potassiumcarbonate in 300 mL dichloromethane while being cooled. The mixture isstirred overnight at ambient temperature and then combined with water.The organic phase is washed with water, dried and evaporated down. Theresidue is stirred with diethyl ether. Yield: 18 g (69%); massspectroscopy [M+H]⁺=171.

b) 4-fluoro-N-1-methyl-benzene-1,2-diamine: 22 g (0.12 mol)(4-fluoro-2-nitro-phenyl)-methyl-amine in 250 mL ethanol arehydrogenated at 4 bar hydrogen pressure with palladium on charcoal ascatalyst. The catalyst is separated off and the solvent is distilledoff. The oil remaining is purified by chromatography (silica gel,hexane/ethyl acetate gradient). Yield: 9 g (50%); mass spectroscopy[M+H]⁺=141.

c) 5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one: 13.0 g (92.1 mmol)4-fluoro-N-1-methyl-benzene-1,2-diamine are reacted with trichloromethylchloroformate analogously to the method described for Intermediate 7c.After stirring in diethyl ether the product is isolated. Yield: 6.0 g(39%); mass spectroscopy: [M+H]⁺=167.

d)5-fluoro-1-methyl-3-(4-methyl-4-nitro-pentyl)-1,3-dihydro-benzimidazol-2-one:First of all 0.624 g (13.9 mmol) 60% sodium hydride and then, whilecooling, 4.6 g (17.8 mmol) 1-iodo-4-methyl-4-nitro-pentane in 10 mL DMFare added to a solution of 2.1 g (12.6 mmol)5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one in DMF. The reactionmixture is stirred overnight at ambient temperature, then poured ontowater and extracted with diethyl ether. The organic phases areevaporated down and the residue is recrystallised from isopropylether.Yield: 1.8 g (48%); mass spectroscopy [M+H]⁺=296.

e)3-(4-amino-4-methyl-pentyl)-5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one:1.8 g (6.09 mmol)5-fluoro-1-methyl-3-(4-methyl-4-nitro-pentyl)-1,3-dihydro-benzimidazol-2-onein 50 mL methanol are hydrogenated at 3 bar hydrogen pressure with Raneynickel as catalyst. The catalyst is separated off and the solvent isdistilled off. In order to prepare the hydrochloride the residue iscombined with ethanol and hydrochloric acid in diethyl ether.

Yield: 1.5 g (83%, hydrochloride); melting range=225-228° C.; massspectroscopy [M+H]⁺=303.

Intermediate 9:3-(4-amino-4-methyl-pentyl)-4-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one

a) (3-fluoro-2-nitro-phenyl)-methyl-amine: Reaction of 2.0 g (2.6 mmol)2,6-difluoro-nitrobenzene with a 2 molar solution of methylamine in THFanalogously to the method for preparing Intermediate 7a. Yield: 1.8 g(86%); mass spectroscopy: [M+H]⁺=171.

b) 3-fluoro-N-1-methyl-benzene-1,2-diamine: Reduction of 8.0 g (47.0mmol) (3-fluoro-2-nitro-phenyl)-methyl-amine with SnCl₂×2H₂O accordingto the method described for Intermediate 7b. Yield: 4.5 g (68%); massspectroscopy: [M+H]⁺=141.

c) 4-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one: Prepared from 4.5 g(32.1 mmol) 3-fluoro-N-1-methyl-benzene-1,2-diamine analogously to themethod described for Intermediate 7c. Yield: 1.4 g (26%); massspectroscopy: [M+H]⁺=167.

d)4-fluoro-1-methyl-3-(4-methyl-4-nitro-pentyl)-1,3-dihydro-benzimidazol-2-one:Prepared from 1.4 g (8.42 mmol)4-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one analogously to themethod described for Intermediate 7d.

Yield: 1.7 g (68%); mass spectroscopy: [M+H]⁺=296.

e)3-(4-amino-4-methyl-pentyl)-4-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-one:A solution of 2 g (6.7 mmol)4-fluoro-1-methyl-3-(4-methyl-4-nitro-pentyl)-1,3-dihydro-benzimidazol-2-onein methanol is hydrogenated in the presence of Raney nickel at 3 barhydrogen pressure. After separation of the catalyst hydrochloric acid indiethyl ether is added. The hydrochloride precipitated is filtered offand dried.

Yield: 1.5 g (83%, hydrochloride); melting range=230-232° C.; massspectroscopy: [M+H]⁺=303.

Intermediate 10: 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one

a) 1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone: 18 mL fumingnitric acid are added dropwise to a solution of 81.5 g (0.34 mol)1-(5-benzyloxy-2-hydroxy-phenyl)-ethanon in 700 mL acetic acid whilecooling with the ice bath, such that the temperature does not rise above20° C. Then the reaction mixture is stirred for two hours at ambienttemperature, poured onto ice water and filtered. The product isrecrystallised from isopropanol, suction filtered and washed withisopropanol and diisopropylether.

Yield: 69.6 g (72%); mass spectroscopy [M+H]⁺=288.

b) 1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone: 69.5 g (242 mmol)of 1-(5-benzyloxy-2-hydroxy-3-nitro-phenyl)-ethanone are dissolved in1.4 L methanol and hydrogenated at 3 bar and at ambient temperature inthe presence of 14 g rhodium on charcoal (10%) as catalyst. Then thecatalyst is filtered off and the filtrate is evaporated down. Theresidue is reacted further without any additional purification.

Yield: 60.0 g (96%), R_(f) value=0.45 (dichloromethane on silica gel).

c) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one: 21.0 mL (258 mmol)chloroacetyl chloride are added dropwise to 60.0 g (233 mmol)1-(3-amino-5-benzyloxy-2-hydroxy-phenyl)-ethanone and 70.0 g (506 mmol)potassium carbonate while cooling with the ice bath. Then the mixture isstirred overnight at ambient temperature and then for 6 hours at refluxtemperature. The hot reaction mixture is filtered, then evaporated downto about 400 mL and combined with ice water. The precipitate formed issuction filtered, dried and purified chromatography on a short silicagel column (dichloromethane:methanol=99:1). The fractions containing theproduct are evaporated down, suspended in isopropanol/diisopropylether,suction filtered and washed with diisopropylether.

Yield: 34.6 g (50%); mass spectroscopy [M+H]⁺=298.

d) 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-one: 13.8 g(46.0 mmol) 8-acetyl-6-benzyloxy-4H-benzo[1,4]oxazin-3-one and 35.3 g(101.5 mmol) benzyltrimethyl-ammonium-dichloriodate are stirred in 250mL dichloroethane, 84 mL glacial acetic acid and 14 mL water for 5 hoursat 65° C. After cooling to ambient temperature the mixture is combinedwith 5% sodium hydrogen sulphite solution and stirred for 30 minutes.The precipitated solid is suction filtered, washed with water anddiethyl ether and dried.

Yield: 13.2 g (86%); mass spectroscopy [M+H]⁺=330/32.

e)6-benzyloxy-8-((R)-2-chloro-1-hydroxy-ethyl)-4H-benzo[1,4]-oxazin-3-one:This is carried out analogously to a method described in the literature(Org. Lett. 2002, 4, 4373-4376). At −15° C. 8 mL of a mixture of formicacid and triethylamine (molar ratio=5:2) are added dropwise to 13.15 g(39.6 mmol) 6-benzyloxy-8-(2-chloro-acetyl)-4H-benzo[1,4]oxazin-3-oneand 25.5 mg (0.04 mmol) Cp*RhCl[(S,S)-TsDPEN](Cp*=pentamethylcyclopentadienyl andTsDPEN=(1S,2S)—N-p-toluenesulphonyl-1,2-diphenylethylenediamine) in 40mL dimethylformamide. The mixture is left for 5 hours at thistemperature with stirring, then 25 mg catalyst are added and the mixtureis stirred overnight at −15° C. The reaction mixture is combined withice water and filtered. The filter residue is dissolved indichloromethane, dried with sodium sulphate and freed from the solvent.The residue is chromatographed (dichloromethane/methanol gradient) andthe product is recrystallised from diethyl ether/diisopropylether.

Yield: 10.08 g (76%); R_(f) value=0.28 (dichloromethane:methanol=50:1 onsilica gel).

f) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-one: 10.06 g (30.1mmol)6-benzyloxy-8-((R)-2-chloro-1-hydroxy-ethyl)-4H-benzo[1,4]-oxazin-3-oneare dissolved in 200 mL dimethylformamide. The solution is combined at0° C. with 40 mL of a 2 molar sodium hydroxide solution and stirred for4 hours at this temperature. The reaction mixture is poured onto icewater, stirred for 15 minutes and then filtered. The solid is washedwith water and dried. Yield: 8.60 g (96%); mass spectroscopy [M+H]⁺=298.

Synthesis of Salt Precursors

General Method 1:1 mmol glyoxal aldehyde or acetal and 1 mmol amine arestirred for 30 minutes in 5 mL tetrahydrofuran at 50° C. The mixture iscooled to 0° C. and under an argon atmosphere 1.5 mL of a 2 molarsolution of lithium borohydride in tetrahydrofuran is added dropwise.The mixture is stirred for 30 min at 0° C., combined with 10 mLdichloromethane and 3 mL water, stirred for another hour at ambienttemperature and then filtered through kieselguhr, while eluting withdichloromethane. The eluate is freed from the solvent and the residue ispurified by chromatography, if necessary. The benzylether thus obtainedis dissolved in methanol and hydrogenated with palladium on charcoal(10%) as catalyst at 2.5 bar and ambient temperature. Then the catalystis separated off and the crude product is purified by chromatography(reverse phase, acetonitrile/water gradient with 0.1% trifluoroaceticacid) or recrystallised from acetonitrile.

General Method 2: 1 mmol glyoxal aldehyde or acetal and 1 mmol amine aresuspended in 5 mL ethanol and heated to 70° C. The resulting solution isstirred for one hour at 70° C. and then cooled to ambient temperature.After the addition of 113 mg (3 mmol) sodium borohydride the mixture isstirred for 3 hours at ambient temperature, combined with 0.7 mLsaturated potassium carbonate solution and stirred for a further 30minutes. It is filtered through aluminium oxide (basic), washedrepeatedly with dichloromethane/methanol 15:1, evaporated down andchromatographed (silica gel; dichloromethane with 0-10%methanol:ammonia=9:1). The benzyl compound thus obtained is dissolved in10 mL methanol and hydrogenated with palladium on charcoal as catalystat 1 bar hydrogen pressure. Then the catalyst is filtered off and thefiltrate is evaporated down.

Salt precursor 1:8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The compound is prepared according to General Method 1 from 357 mg (1mmol)6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 233 mg (1 mmol)1-(3-amino-3-methyl-butyl)-6-methyl-1,3-dihydro-benzimidazol-2-one.

Yield: 170 mg (31%, trifluoroacetate); mass spectroscopy: [M+H]⁺=441.

Salt precursor 2:8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

Prepared according to General Method 1 from 357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-1, 2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 287 mg (1 mmol)1-(3-amino-3-methyl-butyl)-5-trifluoromethyl-1,3-dihydro-benzimidazol-2-one.

Yield: 76 mg (13%, trifluoroacetate); mass spectroscopy: [M+H]⁺=495.

Salt precursor 3:8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 287 mg (1 mmol) 3-(4-amino-4-methyl-pentyl)-3H-benzoxazol-2-one arereacted according to General Method 1. After hydrogenolytic cleaving ofthe benzyl protective group the crude product is isolated, and from thisthe product is obtained by stirring in an acetone/diethyl ether mixture.

Yield: 161 mg (29%, trifluoroacetate); mass spectroscopy: [M+H]⁺=442.

Salt precursor 4:8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

Prepared according to General Method 2 from 357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-1, 2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 233 mg (1 mmol)1-(3-amino-3-methyl-butyl)-3-methyl-1,3-dihydro-benzimidazol-2-one.

Yield: 270 mg (61%); mass spectroscopy: [M+H]⁺=441.

Salt precursor 5:8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

The target compound is prepared according to General Method 2 from 357mg (1 mmol)6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 219 mg (1 mmol)1-(3-amino-3-methyl-butyl)-1,3-dihydro-benzimidazol-2-one.

Yield: 187 mg (44%); mass spectroscopy: [M+H]⁺=427.

Salt precursor 5:R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

a)6-benzyloxy-8-{(R)-2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-one:300 mg (1.01 mmol) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-oneand 250 mg (1.14 mmol)1-(3-amino-3-methyl-butyl)-1,3-dihydro-benzimidazol-2-one in 3 mLtoluene are stirred for 60 minutes at 160° C. in the microwave (EmrysOptimizer made by Personal Chemistry). After cooling the toluene isdecanted off and the residue is chromatographed on a silica gel column.The solid thus obtained (480 mg, 95%) is reacted further without anymore purification. Mass spectroscopy: [M+H]⁺=517.

b)8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehydrochloride: 470 mg (95%, 0.86 mmol)6-benzyloxy-8-{(R)-2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-onein 40 mL methanol are hydrogenated at ambient temperature and at 3 barhydrogen pressure with palladium on charcoal as catalyst (10%). Then thecatalyst is separated off and the filtrate is evaporated down in vacuo.The residue is dissolved in a little methanol/isopropanol and combinedwith 5 molar hydrochloric acid in isopropanol. The precipitated solid isfiltered off, washed with diethyl ether and dried.

Yield: 335 mg (84%); mass spectroscopy: [M+H]⁺=427. The free base can beobtained from the hydrochloride by adding dichloromethane to the latterand extracting it with aqueous potassium carbonate solution.

Salt precursor 6:8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

Prepared according to General Method 2 from 357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 233 mg (1 mmol)1-(4-amino-4-methyl-pentyl)-1,3-dihydro-benzimidazol-2-one.

Yield: 192 mg (44%); mass spectroscopy: [M+H]⁺=441.

Salt precursor 7:8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

This is prepared according to General Method 1 from 357 mg (1 mmol)6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-oneand 220 mg (1 mmol) 3-(3-amino-3-methyl-butyl)-3H-benzoxazol-2-one.

Yield: 227 mg (42%, trifluoroacetate); mass spectroscopy: [M+H]⁺=428.

Salt precursor 8:6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one

a)6-benzyloxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-on:200 mg (0.667 mmol)1-(3-amino-3-methyl-butyl)-4-methoxy-1,3-dihydro-benzimidazol-2-onehydrochloride and 120 μL (0.733 mmol) triethylamine in 5 mL THF arestirred for 30 minutes and then combined with 200 mg (0.666 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one.After 2 hours the reaction mixture is cooled to 10° C. and 60 mg (2.76mmol) lithium borohydride are added. The mixture is stirred for one hourat ambient temperature, then cooled to 10° C. and combined with 15 mLwater. The organic phase is extracted with dichloromethane and thecombined organic extracts are dried and freed from the solvent. The oilremaining is dissolved in ethyl acetate and adjusted to pH 2 withhydrochloric acid in ethyl acetate. The solvent is distilled off and theresidue is stirred with dichloromethane/diethyl ether.

Yield: 130 mg (35%, hydrochloride); mass spectroscopy: [M+H]⁺=561.

b)6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-6-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one:130 mg (0.213 mmol)6-benzyloxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onehydrochloride are dissolved in methanol and hydrogenated at normalpressure with palladium on charcoal as catalyst. The catalyst isfiltered through Celite, the filtrate is freed from the solvent and theresidue is stirred with ethyl acetate. Solid.

Yield: 50 mg (45%, hydrochloride); mass spectroscopy: [M+H]⁺=471.

Salt precursor 9:6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one

Prepared from1-(3-amino-3-methyl-butyl)-5-methoxy-3-methyl-1,3-dihydro-benzimidazol-2-oneand 6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-oneanalogously to the method described for Salt precursor 8. Massspectroscopy: [M+H]⁺=485.

Salt precursor 10:8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

a)6-benzyloxy-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-t-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-one:200 mg (0.754 mmol)3-(4-amino-4-methyl-pentyl)-5-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-onehydrochloride and 237 mg (0.663 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one arereacted analogously to the procedure laid down for Salt precursor 8a.The final purification is carried out by chromatography on a silica gelcolumn. Yield: 164 mg (44%); mass spectroscopy: [M+H]⁺=563.

b)8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one:164 mg (0.274 mmol)6-benzyloxy-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-oneare debenzylated analogously to the procedure laid down for Saltprecursor 8b. For purification the crude product is stirred with ethylacetate. Mass spectroscopy: [M+H]⁺=473.

Salt precursor 11:8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

a)6-benzyloxy-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-t-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-one:200 mg (0.663 mmol)3-(4-amino-4-methyl-pentyl)-4-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-onehydrochloride and 237 mg (0.663 mmol)6-benzyloxy-8-(2-ethoxy-2-hydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one arereacted analogously to the procedure laid down for preparing Saltprecursor 8a. The final purification of the product is carried out bychromatography on a silica gel column. Yield: 68 mg (17%); massspectroscopy: [M+H]⁺=563.

b)8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-t-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one:68 mg (0.121 mmol)6-benzyloxy-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-oneare debenzylated according to the method described for Salt precursor8b. For purification the crude product is stirred in ethyl acetate.Yield: 60 mg; mass spectroscopy: [M+H]⁺=474.

Salt precursor 11:R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one

a)6-benzyloxy-8-{(R)-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-one:595 mg (2.0 mmol) 6-benzyloxy-8-(R)-oxiranyl-4H-benzo[1,4]oxazin-3-oneand 743 mg (2.8 mmol)3-(4-amino-4-methyl-pentyl)-4-fluoro-1-methyl-1,3-dihydro-benzimidazol-2-onein 3.5 mL 2-propanol are stirred at 140° C. in the microwave for 40minutes. Then the solvent is distilled off in vacuo and the residue ispurified on a silica gel column (eluant: dichloromethane/methanolgradient). The corresponding fractions are combined and freed from thesolvent. White solid. Yield: 800 mg (71%), mass spectroscopy:[M+H]⁺=563.

b)8-{(R)-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-t-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one:750 mg (1.33 mmol)6-benzyloxy-8-{(R)-2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-4H-benzo[1,4]oxazin-3-onein 15 mL methanol are hydrogenated at ambient temperature and 3 barhydrogen pressure in the presence of Raney nickel. The catalyst isfiltered off and the filtrate is freed from the solvent. White solid.Yield: 550 mg (87%), mass spectroscopy: [M+H]⁺=473.

For syntheses that do not yield an enantiomerically pure product, theR-enantiomer according to the invention may be obtained from theracemate using methods known per se in the prior art.

Synthesis of Salts

The compounds of formula 1 may be prepared according to the followinggeneral procedure.

a) Maleate: 1.17 mmol of one of the compounds of the salt precursors1-11 are dissolved in 5 ml of ethanol at 60° C. After the addition of0.14 g (1.17 mmol) maleic acid the mixture is cooled to ambienttemperature and stirred for 4 hours. The solid formed is filtered off,washed with ethanol and dried for 12 hours at 45° C.

Yield: about 80-90% of theory, the cation to anion stoichiometry is 1:1.

b) L-(+)-tartrate: 35.2 mmol of one of the compounds of the saltprecursors 1-11 are dissolved in 150 ml of ethanol at ambienttemperature. The solution is heated to 60° C. and a solution of 5.3 g(35.2 mmol) L-(+)-tartaric acid in 40 ml of ethanol is added dropwise.The mixture is cooled to ambient temperature over 6 hours and theresulting solid is filtered. The isolated solid is washed with 40 ml ofethanol and dried for 12 hours at 45° C.

Yield: about 65-75% of theory, the cation to anion stoichiometry is 1:1.

c) Hemi-ethanedisulphonate: 3.52 mmol of one of the compounds of thesalt precursors 1-11 are dissolved in 15 ml boiling ethanol and mixedwith 0.67 g (3.52 mmol) ethanedisulphonic acid. The mixture is refluxedfor 1 hour and then cooled to ambient temperature. After 12 hours atambient temperature the solid formed is filtered off, washed with 10 mlof ethanol and dried for 12 hours at 45° C.

Yield: about 40-50% of theory, the cation to anion stoichiometry is 2:1.

The compounds named below may be prepared according to theabove-mentioned processes a-c:

Example 1R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 2R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 3R-8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 4R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 5R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 6R-8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 7R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 8R-6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onemaleate Example 9R-6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onemaleate Example 10R-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 11R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate Example 12R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 13R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 14R-8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 15R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 16R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 17R-8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 18R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 19R-6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onetartrate Example 20R-6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onetartrate Example 21R-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 22R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate Example 23R-8-{2-[1,1-dimethyl-3-(6-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 24R-8-{2-[1,1-dimethyl-3-(2-oxo-5-trifluoromethyl-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 25R-8-{2-[1,1-dimethyl-4-(2-oxo-benzoxazol-3-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 26R-8-{2-[1,1-dimethyl-3-(3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 27R-8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 28R-8-{2-[1,1-dimethyl-4-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 29R-8-{2-[1,1-dimethyl-3-(2-oxo-benzoxazol-3-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 30R-6-hydroxy-8-{1-hydroxy-2-[4-(4-methoxy-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 31R-6-hydroxy-8-{1-hydroxy-2-[4-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-ethyl}-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 32R-8-{2-[4-(6-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate Example 33R-8-{2-[4-(7-fluoro-3-methyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-1,1-dimethyl-butylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate

X-Ray Powder Diagram Relating to Example 5

Parameters of the X-ray powder diffractometer used for the measurement:STOE Stadi P X-ray powder diffractometer with a location-sensitivedetector in transmission mode with a curved germanium (111) primarymonochromator; wavelength used: CuK_(α1) with λ=1.540598 Å; powercapacity of the X-ray tube: 40 kV, 40 mA; recording range: 3-40°2Θ).

The following Table shows the characteristic X-ray reflections withintensities (standardised, up to 40° 20) for the Example specified. Asthe skilled man knows, the intensities of the reflections may varydepending on the preparation of the samples. The intensities given belowwere recorded in one measurement of the Example specified above andcannot be applied to every other measurement. 2Θ [°] d_(hkl) [Å]intensity I/I_(o) [%] 3.83 23.02 100 9.73 9.09 44 10.26 8.62 6 11.197.90 10 11.57 7.64 23 12.26 7.21 83 14.60 6.06 48 14.98 5.91 38 15.485.72 11 16.47 5.38 5 17.45 5.08 70 17.79 4.98 19 18.20 4.87 56 19.144.63 29 19.88 4.46 84 21.46 4.14 6 22.70 3.91 53 23.33 3.81 56 24.223.67 76 25.29 3.52 6 26.09 3.41 18 26.76 3.33 9 27.50 3.24 56 28.84 3.0914 29.17 3.06 22 30.81 2.90 11 31.33 2.85 8 31.81 2.81 4 32.42 2.76 732.76 2.73 6 33.74 2.65 4 34.58 2.59 14 35.17 2.55 11 35.54 2.52 6 35.942.50 4 36.52 2.46 3 37.65 2.39 4 38.79 2.32 6 39.54 2.28 8Thermoanalysis (DSC/TG) Relating to Example 5

Technical data relating to the thermoanalytical DSC device used: DSC 822made by Mettler Toledo; heating rate: 10 K/min; type of crucible:perforated aluminium crucible; atmosphere: N₂, 80 ml/min flux; weight:12.4 mg.

Technical data relating to the thermoanalytical TG device used: TGA/SDTA851 made by Mettler Toledo with IR coupling (Nicolet FT-IR 4700) foranalysing the volatile fractions driven off, heating rate: 10 K/min;type of crucible: open aluminium oxide crucible; atmosphere: N₂, 20ml/min flux; weight: 27.8 mg.

The above Example for which the X-ray powder diffractogram was alsoproduced has an endothermic maximum at about 237° C. with decomposition(FIG. 1).

X-Ray Powder Diagram Relating to Example 16

Parameters of the X-ray powder diffractometer used for the measurement:STOE Stadi P X-ray powder diffractometer with a location-sensitivedetector in transmission mode with a curved germanium (111) primarymonochromator; wavelength used: CuK_(α1) with λ=1.540598 Å; powercapacity of the X-ray tube: 40 kV, 40 mA; recording range: 3-40°2Θ).

The following Table shows the characteristic X-ray reflections withintensities (standardised, up to 40° 20) for the Example specified. Asthe skilled man knows, the intensities of the reflections may varydepending on the preparation of the samples. The intensities given belowwere recorded in one measurement of the Example specified above andcannot be applied to every other measurement. 2Θ [°] d_(hkl) [Å]intensity I/I_(o) [%] 3.97 22.23 100 10.44 8.47 18 11.24 7.86 15 11.947.41 17 13.22 6.69 27 14.87 5.95 6 15.73 5.63 95 15.96 5.55 14 16.355.42 22 16.88 5.25 46 17.36 5.11 31 18.30 4.84 63 19.27 4.60 3 19.964.44 7 20.34 4.36 34 20.95 4.24 19 21.26 4.18 32 21.42 4.14 14 22.373.97 7 22.61 3.93 12 22.76 3.90 18 23.05 3.86 67 23.64 3.76 19 24.003.71 8 24.40 3.65 10 24.77 3.59 13 25.25 3.52 18 25.58 3.48 49 25.763.46 19 26.07 3.41 6 26.49 3.36 29 27.16 3.28 15 27.41 3.25 8 27.67 3.2222 28.01 3.18 8 28.52 3.13 4 29.03 3.07 4 29.36 3.04 8 29.88 2.99 1030.21 2.96 5 30.85 2.90 3 31.76 2.81 5 31.96 2.80 8 32.45 2.76 10 32.852.72 11 33.73 2.66 7 34.23 2.62 10 34.99 2.56 9 35.63 2.52 3 36.54 2.465 37.05 2.42 4 37.28 2.41 4 37.71 2.38 3 38.49 2.34 8Thermoanalysis (DSC/TG) Relating to Example 16

Technical data relating to the thermoanalytical DSC device used: DSC 822made by Mettler Toledo; heating rate: 10 K/min; type of crucible:perforated aluminium crucible; atmosphere: N₂, 80 ml/min flux; weight:12.4 mg.

Technical data relating to the thermoanalytical TG device used: TGA/SDTA851 made by Mettler Toledo with IR coupling (Nicolet FT-IR 4700) foranalysing the volatile fractions driven off; heating rate: 10 K/min;type of crucible: open aluminium oxide crucible; atmosphere: N₂, 20ml/min flux; weight: 27.8 mg.

The above Example for which the X-ray powder diffractogram was alsoproduced has an endothermic maximum at about 234° C. with decomposition(FIG. 2).

X-Ray Powder Diagram Relating to Example 27

Parameters of the X-ray powder diffractometer used for the measurement:STOE Stadi P X-ray powder diffractometer with a location-sensitivedetector in transmission mode with a curved germanium (111) primarymonochromator; wavelength used: CuK_(α1) with λ=1.540598 Å; powercapacity of the X-ray tube: 40 kV, 40 mA; recording range: 3-40°2Θ).

The following Table shows the characteristic X-ray reflections withintensities (standardised, up to 40° 2Θ) for the Example specified. Asthe skilled man knows, the intensities of the reflections may varydepending on the preparation of the samples. The intensities given belowwere recorded in one measurement of the Example specified above andcannot be applied to every other measurement. 2 Θ [°] d_(hkl) [Å]intensity I/I_(o) [%] 7.25 12.18 90 8.22 10.75 88 8.90 9.92 24 9.46 9.3448 11.36 7.78 14 12.76 6.93 67 13.20 6.70 14 14.52 6.09 52 14.82 5.97 2515.58 5.68 40 16.51 5.36 46 16.82 5.27 28 17.20 5.15 15 18.08 4.90 2118.89 4.69 79 20.02 4.43 77 20.25 4.38 35 20.88 4.25 24 21.18 4.19 3721.87 4.06 24 22.16 4.01 16 22.66 3.92 11 23.16 3.84 37 23.70 3.75 10024.48 3.63 24 25.82 3.45 65 26.07 3.42 25 26.59 3.35 10 26.94 3.31 827.65 3.22 8 28.77 3.10 15 29.61 3.01 19 29.89 2.99 24 32.69 2.74 1433.90 2.64 8 34.79 2.58 11 36.58 2.45 8 36.84 2.44 12 30.21 2.96 5 30.852.90 3 31.76 2.81 5 31.96 2.80 8 32.45 2.76 10 32.85 2.72 11 33.73 2.667 34.23 2.62 10 34.99 2.56 9 35.63 2.52 3 36.54 2.46 5 37.05 2.42 437.28 2.41 4 37.71 2.38 3 38.49 2.34 8 39.13 2.30 6Thermoanalysis (DSC/TG) Relating to Example 27

Technical data relating to the thermoanalytical DSC device used: DSC 822made by Mettler Toledo; heating rate: 10 K/min; type of crucible:perforated aluminium crucible; atmosphere: N₂, 80 ml/min flux; weight:12.4 mg.

Technical data relating to the thermoanalytical TG device used: TGA/SDTA851 made by Mettler Toledo with IR coupling (Nicolet FT-IR 4700) foranalysing the volatile fractions driven off; heating rate: 10 K/min;type of crucible: open aluminium oxide crucible; atmosphere: N₂, 20ml/min flux; weight: 27.8 mg.

The above Example for which the X-ray powder diffractogram was alsoproduced has an endothermic maximum at about 209° C. with decompositionand is in the form of the hydrate (FIG. 3).

Combinations

The compounds of formula 1 may be used on their own or in combinationwith other active substances of formula 1. If desired the compounds offormula 1 may also be used in combination with W, where W denotes apharmacologically active substance and (for example) is selected fromamong the betamimetics, anticholinergics, corticosteroids,PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PJ3-kinase inhibitors. Moreover,double or triple combinations of W may be combined with the compounds offormula 1. Combinations of W might be, for example:

-   -   W denotes a betamimetic, combined with an anticholinergic,        corticosteroid, PDE4-inhibitor, EGFR-inhibitor or        LTD4-antagonist,    -   W denotes an anticholinergic, combined with a betamimetic,        corticosteroid, PDE4-inhibitor, EGFR-inhibitor or        LTD4-antagonist,    -   W denotes a corticosteroid, combined with a PDE4-inhibitor,        EGFR-inhibitor or LTD4-antagonist    -   W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or        LTD4-antagonist    -   W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selectedfrom among albuterol, arformoterol, bambuterol, bitolterol, broxaterol,carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol,terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81,KUL-1248 and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide-   5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one-   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone-   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol-   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazole-3-yl]-2-methyl-2-butylamino}ethanol-   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on-   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol-   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl    4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic    acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1    dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one-   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric    acid-   8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H    -benzo[1,4]oxazin-3-one-   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the acid addition salts of the    betamimetics are preferably selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, preferably the bromide salt, oxitropium salts,preferably the bromide salt, flutropium salts, preferably the bromidesalt, ipratropium salts, preferably the bromide salt, glycopyrroniumsalts, preferably the bromide salt, trospium salts, preferably thechloride salt, tolterodine. In the above-mentioned salts the cations arethe pharmacologically active constituents. As anions the above-mentionedsalts may preferably contain the chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzo ate orp-toluenesulphonate, while chloride, bromide, iodide, sulphate,methanesulphonate or p-toluenesulphonate are preferred as counter-ions.Of all the salts the chlorides, bromides, iodides and methanesulphonatesare particularly preferred.

Other preferred anticholinergics are selected from among the salts offormula AC-1

wherein X⁻ denotes an anion with a single negative charge, preferably ananion selected from among the fluoride, chloride, bromide, iodide,sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,citrate, fumarate, tartrate, oxalate, succinate, benzoate andp-toluenesulphonate, preferably an anion with a single negative charge,particularly preferably an anion selected from among the fluoride,chloride, bromide, methanesulphonate and p-toluenesulphonate,particularly preferably bromide, optionally in the form of theracemates, enantiomers or hydrates thereof. Of particular importance arethose pharmaceutical combinations which contain the enantiomers offormula AC-1-ene

wherein X⁻ may have the above-mentioned meanings. Other preferredanticholinergics are selected from the salts of formula AC-2

wherein R denotes either methyl or ethyl and wherein X⁻ may have theabove-mentioned meanings. In an alternativen embodiment the compound offormula AC-2 may also be present in the form of the free base AC-2-base.

Other specified compounds are:

-   -   tropenol 2,2-diphenylpropionate methobromide,    -   scopine 2,2-diphenylpropionate methobromide,    -   scopine 2-fluoro-2,2-diphenylacetate methobromide,    -   tropenol 2-fluoro-2,2-diphenylacetate methobromide;    -   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide,    -   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide,    -   tropenol 4,4′-difluorobenzilate methobromide,    -   scopine 4,4′-difluorobenzilate methobromide,    -   tropenol 3,3′-difluorobenzilate methobromide,    -   scopine 3,3′-difluorobenzilate methobromide;    -   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide;    -   tropenol 9-fluoro-fluorene-9-carboxylate methobromide;    -   scopine 9-hydroxy-fluorene-9-carboxylate methobromide;    -   scopine 9-fluoro-fluorene-9-carboxylate methobromide;    -   tropenol 9-methyl-fluorene-9-carboxylate methobromide;    -   scopine 9-methyl-fluorene-9-carboxylate methobromide;    -   cyclopropyltropine benzilate methobromide;    -   cyclopropyltropine 2,2-diphenylpropionate methobromide;    -   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate        methobromide;    -   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide;    -   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide;    -   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate        methobromide;    -   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide.    -   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide;    -   scopine 9-hydroxy-xanthene-9-carboxylate methobromide;    -   tropenol 9-methyl-xanthene-9-carboxylate-methobromide;    -   scopine 9-methyl-xanthene-9-carboxylate-methobromide;    -   tropenol 9-ethyl-xanthene-9-carboxylate methobromide;    -   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide;    -   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,

The above-mentioned compounds may also be used as salts within the scopeof the present invention, wherein instead of the methobromide the saltsmetho-X are used, wherein X may have the meanings given hereinbefore forX⁻.

As corticosteroids it is preferable to use compounds selected from amongprednisolone, prednisone, butixocort propionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, ST-26 and

-   (S)-fluoromethyl    6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate-   (S)-(2-oxo-tetrahydro-furan-3    S-yl)6,9-difluoro-[1-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,-   etiprednol-dichloroacetate    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the salts and    derivatives thereof, the solvates and/or hydrates thereof. Any    reference to steroids includes a reference to any salts or    derivatives, hydrates or solvates thereof which may exist. Examples    of possible salts and derivatives of the steroids may be: alkali    metal salts, such as for example sodium or potassium salts,    sulphobenzoates, phosphates, isonicotinates, acetates, propionates,    dihydrogen phosphates, palmitates, pivalates or furoates.

PDE4-inhibitors which may be used are preferably compounds selected fromamong enprofyllin, theophyllin, roflumilast, ariflo (cilomilast),tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418,Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281(GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585,V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370 and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide-   (−)_(p)-[(4aR*,    10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N²-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone-   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic    acid]-   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one-   cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol]-   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine-   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts thereof, the    solvates and/or hydrates thereof. According to the invention the    acid addition salts of the betamimetics are preferably selected from    among the hydrochloride, hydrobromide, hydriodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001,MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic    acid,-   1-(((1(R)-3    (3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic    acid-   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic    acid    optionally in the form of the racemates, enantiomers or    diastereomers thereof and optionally in the form of the    pharmacologically acceptable acid addition salts, solvates and/or    hydrates thereof. According to the invention the acid addition salts    of the betamimetics are preferably selected from among the    hydrochloride, hydrobromide, hydroiodide, hydrosulphate,    hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate,    hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate,    hydroxalate, hydrosuccinate, hydrobenzoate and    hydro-p-toluenesulphonate. By salts or derivatives which the    LTD4-antagonists may optionally be capable of forming are meant, for    example: alkali metal salts, such as for example sodium or potassium    salts, alkaline earth metal salts, sulphobenzoates, phosphates,    isonicotinates, acetates, propionates, dihydrogen phosphates,    palmitates, pivalates or furoates.

EGFR-inhibitors which may be used are preferably compounds selected fromamong cetuximab, trastuzumab, ABX-EGF, Mab ICR-62 and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline-   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline-   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydro    furan-2-yl)methoxy]-quinazo line-   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline-   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline-   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the preferred acid addition salts of the    betamimetics are selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

The dopamine agonists used are preferably compounds selected from amongbromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride,pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid andviozan, optionally in the form of the racemates, enantiomers,diastereomers thereof and optionally in the form of thepharmacologically acceptable acid addition salts, solvates or hydratesthereof. According to the invention the preferred acid addition salts ofthe betamimetics are selected from among the hydrochloride,hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selectedfrom among epinastine, cetirizine, azelastine, fexofenadine,levocabastine, loratadine, mizolastine, ketotifen, emedastine,dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine,doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine,promethazine, ebastine, desloratidine and meclozine, optionally in theform of the racemates, enantiomers, diastereomers thereof and optionallyin the form of the pharmacologically acceptable acid addition salts,solvates or hydrates thereof. According to the invention the preferredacid addition salts of the betamimetics are selected from among thehydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate,hydrobenzoate and hydro-p-toluenesulphonate.

The PAF-antagonists used are preferably compounds selected from among

-   4-(2-chlorophenyl)-9-methyl-2-[3    (4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-   6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine,    optionally in the form of the racemates, enantiomers, diastereomers    thereof and optionally in the form of the pharmacologically    acceptable acid addition salts, solvates or hydrates thereof.    According to the invention the preferred acid addition salts of the    betamimetics are selected from among the hydrochloride,    hydrobromide, hydriodide, hydrosulphate, hydrophosphate,    hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,    hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,    hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate.    Formulations

Suitable pharmaceutical compositions and formulation for administeringthe compounds of formula 1 include for example tablets, capsules,suppositories, solutions, powders etc. The content of thepharmaceutically active compound(s) should be in the range from 0.05 to90 wt.-%, preferably 0.1 to 50 wt.-% of the composition as a whole.Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanilline or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions are prepared in the usual way, e.g. with the addition ofisotonic agents, preservatives such as p-hydroxybenzoates or stabiliserssuch as alkali metal salts of ethylenediaminetetraacetic acid,optionally using emulsifiers and/or dispersants, while if water is usedas diluent, for example, organic solvents may optionally be used assolubilisers or dissolving aids, and the solutions may be transferredinto injection vials or ampoules or infusion bottles.

Capsules containing the compounds of formula 1 according to theinvention may for example be prepared by mixing the active substanceswith inert carriers such as lactose or sorbitol and packing them intogelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof. Excipients which may be used include, forexample, water, pharmaceutically acceptable organic solvents such asparaffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut orsesame oil), mono- or polyfunctional alcohols (e.g. ethanol orglycerol), carriers such as e.g. natural mineral powders (e.g. kaolins,clays, talc, chalk), synthetic mineral powders (e.g. highly dispersedsilicic acid and silicates), sugars (e.g. cane sugar, lactose andglucose), emulsifiers (e.g. lignin, spent sulphite liquors,methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g.magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

For oral use the tablets may obviously contain, in addition to thecarriers specified, additives such as sodium citrate, calcium carbonateand dicalcium phosphate together with various additional substances suchas starch, preferably potato starch, gelatine and the like. Lubricantssuch as magnesium stearate, sodium laurylsulphate and talc may also beused to produce the tablets. In the case of aqueous suspensions theactive substances may be combined with various flavour enhancers orcolourings in addition to the above-mentioned excipients.

Use of the compounds of formula 1 for the treatment of respiratorycomplaints can be administered by inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions. Within the scope of the presentinvention, the term propellant-free inhalable solutions also includesconcentrates or sterile ready-to-use inhalable solutions.

The compounds of formula 1 may be used in crystalline form according tothe invention and used to prepare powders for inhalation. The inhalablepowders which may be used according to the invention may contain thecrystalline compounds of formula 1 either on their own or in admixturewith suitable physiologically acceptable excipients.

If the active ingredients are present in admixture with physiologicallyacceptable excipients, the following physiologically acceptableexcipients may be used to prepare these inhalable powders according tothe invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients. Preferably, mono- or disaccharides are used, while theuse of lactose or glucose is preferred, particularly, but notexclusively, in the form of their hydrates. For the purposes of theinvention, lactose is the particularly preferred excipient, whilelactose monohydrate is most particularly preferred.

Within the scope of the inhalable powders according to the invention theexcipients have a maximum average particle size of up to 250 μm,preferably between 10 and 150 μm, most preferably between 15 and 80 μm.In some cases it may seem appropriate to add finer excipient fractionswith an average particle size of 1 to 9 μm to the excipients mentionedabove. These finer excipients are also selected from the group ofpossible excipients listed hereinbefore. Finally, in order to preparethe inhalable powders according to the invention, micronised activesubstance, preferably with an average particle size of 0.5 to 10 μm,more preferably from 1 to 5 μm, is added to the excipient mixture.Processes for producing the inhalable powders according to the inventionby grinding and micronising and finally mixing the ingredients togetherare known from the prior art.

The inhalable powders according to the invention may be administeredusing inhalers known from the prior art.

The inhalation aerosols containing propellant gas according to theinvention may contain dissolved in the propellant gas or in dispersedform. The propellant gases which may be used to prepare the inhalationaerosols are known from the prior art. Suitable propellant gases areselected from among hydrocarbons such as n-propane, n-butane orisobutane and halohydrocarbons such as fluorinated derivatives ofmethane, ethane, propane, butane, cyclopropane or cyclobutane. Theabove-mentioned propellant gases may be used on their own or inadmixture. Particularly preferred propellant gases are halogenatedalkane derivatives selected from TG134a and TG227 and mixtures thereof.

The propellant-driven inhalation aerosols may also contain otheringredients such as co-1-solvents, stabilisers, surfactants,antioxidants, lubricants and pH adjusters. All these ingredients areknown in the art.

The propellant-driven inhalation aerosols mentioned above may beadministered using inhalers known in the art (MDIs=metered doseinhalers).

The dosage of the compounds according to the invention is naturallyhighly dependent on the method of administration and the complaint whichis being treated. When administered by inhalation the compounds of theformula are characterised by a high potency even at doses in the μgrange. The compounds of the formula may also be used effectively abovethe μg range. The dosage may then be in the milligram range, forexample.

In another aspect the present invention relates to the above-mentionedpharmaceutical formulations (compositions) as such, which arecharacterised in that they contain a compound of formula 1, in theabove-mentioned pharmaceutical formulations administered by inhalation.

The following examples of formulations illustrate the present inventionwithout restricting its scope:

Examples of Pharmaceutical Formulations A) Tablets per tablet activesubstance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate  5 mg 500 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B) Tablets per tablet activesubstance 80 mg corn starch 190 mg lactose 55 mg microcrystallinecellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size. C)Coated tablets per coated tablet Active substance 5 mg Corn starch 41.5mg Lactose 30 mg Polyvinylpyrrolidone 3 mg Magnesium stearate 0.5 mg 80mg

The active substance, corn starch, lactose and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax. D) Capsules per capsule Active substance 50 mg Corn starch268.5 mg Magnesium stearate 1.5 mg 320 mg

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules. E) Ampoule solution active substance 50 mgsodium chloride 50 mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50mg of active substance. F) Suppositories Active substance  50 mg Solidfat 1650 mg 1700 mg

The hard fat is melted. At 40° C. the ground active substance ishomogeneously dispersed therein. It is cooled to 38° C. and poured intoslightly chilled suppository moulds. G) Oral suspension active substance50 mg hydroxyethylcellulose 50 mg sorbic acid 5 mg sorbitol (70%) 600 mgglycerol 200 mg flavouring 15 mg water ad 5 ml

Distilled water is heated to 70° C. Hydroxyethyl-cellulose is dissolvedtherein with stirring. After the addition of sorbitol solution andglycerol the preparation is cooled to ambient temperature. At ambienttemperature the sorbic acid, flavouring and substance are added. Thesuspension is evacuated with stirring to eliminate any air.

1. Enantiomerically pure compounds of formula 1

wherein: n denotes 1, 2, 3 or 4; X denotes CH₂, CO, NR², S or O; Bdenotes a double-bonded group of formula CR³R⁴—O; R¹ denotes H,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₁₋₆-haloalkyl,O—C₁₋₆-haloalkyl, halogen, OH, CN, NO₂, O—C₁₋₆-alkyl, COOH orCOO—C₁₋₄-alkyl; R² denotes H, C₁₋₆-alkyl, C₁₋₄-alkylene-C₆₋₁₀-aryl orC₁₋₄-alkylene-C₃₋₆-cycloalkyl; R³ denotes H or C₁₋₆-alkyl; R⁴ denotes Hor C₁₋₆-alkyl; Y^(m-) denotes an anion with m negative charges,preferably an anion with m negative charges selected from amongchloride, bromide, iodide, sulphate, phosphate, methanesulphonate,nitrate, maleate, acetate, benzoate, citrate, salicylate,trifluoroacetate, fumarate, tartrate, oxalate, succinate,ethanedisulphonate, propanedisulphonate, benzoate andp-toluenesulphonate; and m denotes 1 or 2 optionally in the form of thetautomers, mixtures of the tautomers, hydrates or solvates thereof. 2.Enantiomerically pure compounds of according to claim 1, wherein: ndenotes 2 or 3; X denotes CH₂, CO, NR², S or O; B denotes adouble-bonded group of formula CR³R⁴—O; R¹ denotes H, C₁₋₆-alkyl,C₁₋₆-haloalkyl, C₃₋₆-cycloalkyl, halogen, OH, CN, NO₂, O—C₁₋₆-alkyl,COOH or COO—C₁₋₄-alkyl; R² denotes H, C₁₋₄-alkyl, orC₃₋₆-cycloalkyl-methyl; R³ denotes H or methyl; R⁴ denotes H or methyl;Y^(m-) denotes an anion with m negative charges, preferably an anionwith m negative charges selected from among chloride, bromide, iodide,sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate,oxalate, succinate, ethanedisulphonate, benzoate andp-toluenesulphonate; and m denotes 1 or 2; optionally in the form of thetautomers, mixtures of the tautomers, hydrates or solvates thereof. 3.Enantiomerically pure compounds according to claim 1, wherein: n denotes2 or 3; X denotes CH₂, CO, NR², S or O; B denotes a double-bonded groupof formula CR³R⁴—O; R¹ denotes H, methyl, ethyl, propyl, CF₃, CH₂F,CH₂CF₃, fluorine, chlorine, bromine, OH, methoxy, ethoxy, COOH or COOMe;R² denotes H, methyl, ethyl or propyl; R³ denotes H or methyl; R⁴denotes H or methyl; Y^(m-) denotes an anion with m negative charges,preferably an anion with m negative charges selected from amongchloride, bromide, iodide, sulphate, phosphate, methanesulphonate,nitrate, maleate, acetate, benzoate, citrate, salicylate,trifluoroacetate, fumarate, tartrate, oxalate, succinate,ethanedisulphonate, benzoate and p-toluenesulphonate; and m denotes 1 or2; optionally in the form of the tautomers, mixtures of the tautomers,hydrates or solvates thereof.
 4. Enantiomerically pure compoundsaccording to claim 1, wherein: n denotes 2 or 3; X denotes CH₂, CO, NR²,S or O; B denotes a double-bonded group of formula CH₂—O; R¹ denotes H,methyl, ethyl, propyl, CF₃, CH₂F, CH₂CF₃, fluorine, chlorine, bromine,OH, methoxy, ethoxy, COOH or COOMe; R² denotes H, methyl, ethyl orpropyl; Y^(m-) denotes an anion with m negative charges, preferably ananion with m negative charges selected from among chloride, bromide,iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate,acetate, benzoate, citrate, salicylate, trifluoroacetate, fumarate,tartrate, oxalate, succinate, ethanedisulphonate, benzoate andp-toluenesulphonate; and m denotes 1 or 2; optionally in the form of thetautomers, mixtures of the tautomers, hydrates or solvates thereof. 5.Enantiomerically pure compounds according to claim 1, wherein: n denotes2 or 3; X denotes NR² or 0; B denotes a double-bonded group of formulaCH₂—O; R¹ denotes H, methyl, ethyl, propyl, CF₃, CH₂F or CH₂CF₃; R²denotes H, methyl, ethyl or propyl; Y^(m-) denotes an anion with mnegative charges, preferably an anion with m negative charges selectedfrom among chloride, bromide, iodide, sulphate, phosphate,methanesulphonate, nitrate, maleate, acetate, benzoate, citrate,salicylate, trifluoroacetate, fumarate, tartrate, oxalate, succinate,ethanedisulphonate, benzoate and p-toluenesulphonate; and m denotes 1 or2 optionally in the form of the tautomers, mixtures of the tautomers,hydrates or solvates thereof.
 6. Enantiomerically pure compoundsaccording to claim 1, wherein, said compounds are in crystalline form.7. Enantiomerically pure compounds according to claim 1, wherein thecompound is Crystalline8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onemaleate.
 8. The compound according to claim 7, comprising an endothermicmaximum at 237° C.
 9. The compound according to claim 7, comprisingX-ray reflections at d=4.64 Å and 4.75 Å.
 10. Enantiomerically purecompounds according to claim 1, wherein the compound is Crystalline8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onetartrate.
 11. The compound according to claim 10, comprising anendothermic maximum at 234° C.
 12. The compound according to claim 10,comprising X-ray reflections at d=4.64 Å and 4.75 Å. 13.Enantiomerically pure compounds according to claim 1, wherein thecompound is Crystalline8-{2-[1,1-dimethyl-3-(2-oxo-2,3-dihydro-benzimidazol-1-yl)-propylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-onehemi-ethanedisulphonate
 14. The compound according to claim 13,comprising an endothermic maximum at 209° C.
 15. The compound accordingto claim 13, comprising X-ray reflections at d=4.64 Å and 4.75 Å. 16.Enantiomerically pure compounds according toclaim 1, wherein saidcompound is the active ingredient in pharmaceutical compositions. 17.Enantiomerically pure compounds according to claim 16, wherein thepharmaceutical composition comprises a treatment for respiratorycomplaints.
 18. Enantiomerically pure compounds according to claim 1,wherein: n denotes 2 or 3; X denotes CH₂, CO, NR², S or 0; B denotes adouble-bonded group of formula CH₂—O; R¹ denotes H, methyl, ethyl,propyl, CF₃, CH₂F, CH₂CF₃, fluorine, chlorine, bromine, OH, methoxy,ethoxy, COOH or COOMe; R² denotes H, methyl, or cyclopropylmethyl;Y^(m-) denotes an anion with m negative charges, preferably an anionwith m negative charges selected from among chloride, bromide, iodide,sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate,benzoate, citrate, salicylate, trifluoroacetate, fumarate, tartrate,oxalate, succinate, ethanedisulphonate, benzoate andp-toluenesulphonate; and m denotes 1 or 2; optionally in the form of thetautomers, mixtures of the tautomers, hydrates or solvates thereof. 19.Enantiomerically pure compounds according to claim 6, comprisingcrystalline tautomers, crystalline hydrates, and crystalline solvents.